Crosslinked Polyolefins for Biomedical Applications and Method of Making Same

ABSTRACT

The invention relates to a polymer composition that includes a branched alkene which is cationically polymerizable as well as a glass-forming comonomer and/or a vinyl comonomer containing benzocyclobutene as the pendant group. The structure of the polymer composition can take various forms: linear random copolymer, linear block copolymer, star random copolymer, star block copolymer, and other hyperbranched polymers. The copolymer composition can undergoes crosslinking at elevated temperatures (preferably above 180° C.).

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.12/145,704, filed Jun. 25, 2008, and issued as U.S. Pat. No. 8,765,895,on Jul. 1, 2014, which claims benefit of U.S. provisional applicationSer. No. 60/986,384, filed Nov. 8, 2007, both of which are herebyincorporated by reference herein in their entireties.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to polymeric materials. The polymeric materialsare particularly suitable for biomedical applications, such as acomponent of an intraocular lens.

2. State of the Art

Polymers have been used in biomedical applications for a long time.Early in vivo studies on polymeric implants revealed that the polymersare susceptible to degradation in physiological environment and loseintegrity over time. A close scrutiny of the structure andbio-properties relationship led to Pinchuk's discovery of the superiorbiostability of polyisobutylene-based materials. The biomedicalapplication of polyisobutylene-based materials is disclosed in U.S. Pat.Nos. 5,741,331; 6,102,939; 6,197,240; 6,545,097; and 6,855,770, all ofwhich are herein incorporated by reference in their entirety. The firstcommercial application of such materials is the use of SIBS in theTAXUS® Stent of Boston Scientific Corporation, which is regarded as themost successful launch of a biomedical device in history.

SIBS is a thermoforming triblock copolymer consisting of polyisobutylene(PIB) as the rubbery center block and polystyrene (PS) as the hard sideblocks. Due to the immiscibility of PIB and PS, the SIBS material hasmicrophase-separated morphology in which PS phase forms physicalcrosslinks in the matrix of rubbery PIB phase. Due to the thermoplasticnature of the crosslinking, SIBS material creeps and can lose itsdimension. SIBS doesn't withstand the high temperature of autoclavesterilization due to limitation by the glass transition temperature ofPS. As a result, SIBS sterilization is difficult, becausegamma-sterilization breaks down SIBS and ethylene oxide sterilization iscumbersome.

PIB is commonly crosslinked through vulcanization. First, isobutylene iscopolymerized with a small fraction (1-5%) conjugated dienes such asbutadiene, so that there are carbon-carbon double bonds in the backboneproviding sites for vulcanization; second, the isobutylene/butadienecopolymer is heated with sulfur and crosslinked by the sulfur. Toaccelerate the vulcanization process, either the polymer is activated asin the case of halo-butyl rubber, or accelerators are added such asresins, zinc oxide, xanthates and quinoid systems. An extremely fastvulcanization process involves mixing butyl rubber solution with sulfurmonochloride at room temperature (Erman et al, Macromolecules, Vol. 33,2000, 4822-4827). The chemicals used for vulcanization of butyl rubberare toxic to human body. Extraction by solvent is necessary for removalof toxic residuals, but complete extraction is difficult andtime-consuming.

PIB can be crosslinked utilizing silicone chemistry. Kaneka developedtelechelic functional PIB (trade name: Epion) with silyl or allyl endgroups, which can be crosslinked by moisture or adding silanes. Faust etal disclosed a virtually telechelic silyl PIB, which undergoes roomtemperature crosslinking as described in U.S. Pat. No. 6,268,451.

Benzocyclobutene derivates and 1-hexene were analyzed in Fishback etal., “A New Non-Toxic, Curing Agent for Synthetic Polyolefins,”Bio-Medical Materials and Engineering, Vol. 2, pp. 83-87 (1992), hereinincorporated in reference in its entirety. Fishback prepared polymerscontaining 1-hexene, allyl-benzocyclobutene, and a diene, either7-methyl-1,6-octadiene or 5-methyl-1,4-hexadiene, using free-radicalpolymerization techniques. While the polymer showed improved properties,it requires carbon black as a filler, and is polymerizable only throughfree-radical chemistry techniques that necessitate the use of freeradical initiators. Additionally, there is a need to extract thenon-crosslinked polymers to rid the system of the initiators as theinitiators, if not removed, would leave the polymer with an undesirablepurple color.

SUMMARY OF THE INVENTION

The present invention provides a polymeric composition including alkenesand benzocyclobutene-functional olefins that is polymerizable usingliving carbocationic chemistry.

The present invention provides such a polymeric composition that isbiostable, exhibits increased tensile strength, and does not require afiller.

The present invention provides such a polymeric composition that issuitable for many applications.

The present invention provides such a polymeric composition that iscrosslinked in a manner such that it has improved creep resistanceand/or dimensional stability, especially when stressed or at elevatedtemperatures.

The present invention provides such a polymeric composition that doesnot release a small molecule to the environment.

The present invention provides such a polymeric composition that canwithstand high temperature sterilization.

The present invention provides such a polymeric composition that ischemically crosslinked at elevated temperatures (e.g., greater than 180°C.) without addition or evolution of small molecules.

A copolymer composition of the present invention includes, inpolymerized form, a branched alkene which is cationically polymerizableas well as a glass-forming comonomer and/or a vinyl comonomer containingbenzocyclobutene (herein called “BCB”) as the pendant group. Thestructure of the copolymer composition can take various forms: linearrandom copolymer, linear block copolymer, star random copolymer, starblock copolymer, and other hyperbranched polymers and copolymers. Thecopolymer composition preferably undergoes crosslinking reaction atelevated temperatures (preferably above 180° C.).

It will be appreciated that the material of the present invention hasimproved structural characteristics and thus superior physicalproperties (such as creep resistance, heat resistance, dimensionalstability and solvent resistance). By changing the copolymer compositionand structure, materials with variable hardness and crosslinking densitycan be obtained for various biomedical applications. Examples of suchuses include implantable medical devices such as synthetic heart valves,pharmaceutical closure devices, vertebral disks, joint menisci,artificial ligaments, artificial meniscuses, vascular grafts, pacemakerheaders and lead insulators, glaucoma drainage tubes, intraocularlenses, and the like.

The material of the present invention also avoids the release ofmolecules that can cause inflammation when introduced in the body, whichis characteristic of the silyl-terminated PIB of the prior art as itreleases inflammation-introducing small molecules such as methanol,ethanol, acetic acid, chlorine and the like when cured.

Additional objects and advantages of the invention will become apparentto those skilled in the art upon reference to the detailed descriptiontaken in conjunction with the provided figures.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph Gel Permeation Chromatography (GPC) analysis of twosamples, one sample being polyisobutylene and the other sample beingPoly(st-co-4VCB)-PIB-Poly(st-co-4VCB).

FIG. 2 is a spectrum of NMR analysis of thePoly(st-co-4VCB)-PIB-Poly(st-co-4VCB) sample of FIG. 1.

FIG. 3 is a graph GPC RI analysis of three samples of Poly(IB-co-4VCB)at various reaction times.

FIG. 4 is a GPC UV analysis of the Poly(IB-co-4VCB) samples of FIG. 3.

FIG. 5 is a spectrum of NMR analysis of a Poly(IB-co-4VCB) samplesynthesized in accordance with the present invention.

FIG. 6 is a front view of an exemplary embodiment of an intraocular lensdevice in accordance with the present invention.

FIG. 7 is a front view of an alternate embodiment of an intraocular lensdevice in accordance with the present invention.

FIGS. 8A, 8B and 8C illustrate different annular haptic designs that canbe utilized in the embodiment of FIG. 6.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

In accordance with the present invention, a polymer composition suitablefor biomedical applications includes copolymers comprising a pluralityof constitutional units that correspond to one or more branched alkenemonomer species as well as a plurality of constitutional units thatcorrespond to one or more olefin monomer species with pendant BCB groupsand/or a plurality of constitutional units that correspond to one ormore glass-forming monomer species. Typically, each of theseconstitutional units occurs with the copolymer molecule at a frequencyof at least 2 times, and more typically at least 50, 100, 1000 or moretimes. The copolymer composition preferably undergoes crosslinkingreaction at elevated temperatures (preferably above 180° C.).

Due to the strained four-membered ring, benzocyclobutene (BCB) isconverted to o-xylylene at temperatures above 180° C. At such elevatedtemperatures, the BCB group undergoes Diels-Alder reactions withdienophiles to form a six-membered ring, or reacts with itself to forman eight-membered ring. Polymers containing multiple pendant BCB groupsper molecular chain can be thermally crosslinked with or withoutdienophiles. Each crosslink consists of a ring structure ofcarbon-carbon bond, which is more thermally stable than the sulfurbridge in vulcanized polymers and is stronger than the Si—O bond insilicone copolymers. The BCB crosslinking only involves heat. As long asthe polymer is stable at the crosslinking temperature, there is no toxicchemical involved.

An embodiment of this invention relates to a polymer that comprises (a)a plurality of constitutional units that include at least onecationically polymerizable branched alkene monomer; (b) a plurality ofconstitutional units that include at least one cationicallypolymerizable olefin monomer having a pendant benzocyclobutene (BCB)group; and optionally (c) a plurality of constitutional units thatinclude at least one glass-forming monomer, e.g., styrenic monomer or anon-reactive glassy compound. Preferably, the constitutional units ofthe glass-forming monomer are present in the polymer.

The branched alkene monomer may be any monomer that is both branched andcontains a single double bond. The alkene should also be cationicallypolymerizable. Alkenes that are not cationically polymerizable, such as1-hexene, cannot be added to the backbone of the polymer. Similarly,many dienes, such as 1,3-butadiene, cannot propagate in a cationicpolymerization reaction, as the secondary carbon in the vinyl group willfrequently cause the reaction to terminate. As such, dienes aretypically only added to the backbone of a polymer as a cap ormono-addition to a living end. See De et al., “Relative Reactivity of C4Olefins toward the Polyisobutylene Cation,” Macromolecules, 39 (2006)pp. 6861-70. Additionally, effective cationic polymerization can bedifficult using dienes having sterically hindered tertiary carbons.

Examples of suitable branched alkene monomers include C₄-C₁₄ branchedalkenes such as isobutylene, 2-methyl-1-butene, 2-methyl-1-pentene,2-methyl-1-hexene, and beta-pinene. Preferably, the alkene monomer is asmall-chain alkene, such as a C₄-C₇ alkene. More preferably, thebranched alkene monomer is an isoolefin, such as isobutylene,2-methyl-1-butene, or 2-methyl-1-pentene.

The olefin monomer having a pendant BCB group may be any olefin monomercontaining at least one BCB-functional moiety in the olefin. The olefinshould be cationically polymerizable and compatible with the branchedalkene. Suitable olefin monomers having a pendant BCB group include4-vinylbenzocyclobutene, 4-(α-alkylvinyl)benzocyclobutenes such as2-(4-benzocyclobutenyl)-propene and 2-(4-benzocyclobutenyl)-1-butene,and 4-(2-methyl-alkenyl)benzocyclobutenes such as2-methyl-3-(4-benzocyclobutenyl)-1-propene and2-methyl-4-(4-benzocyclobutenyl)-1-butene.

Preferred olefin monomers having a pendant BCB group have the formula

wherein R is hydrogen or an alkyl group (preferably methyl, ethyl, orpropyl) and n is 0. Examples of this type of preferred olefin monomerinclude 4-vinylbenzocyclobutene and 2-(4-benzocyclobutenyl)-propene.

Preferred olefin monomers having a pendant BCB group also includecompounds having the same formula

but wherein R is an alkyl group (preferably methyl, ethyl, or propyl)and n is an integer ranging from 1-3. Examples of this type of preferredolefin monomers include 2-methyl-3-(4-benzocyclobutenyl)-1-propene and2-methyl-4-(4-benzocyclobutenyl)-1-butene.

As can be seen from the above formulas, which are identical, olefinmonomers where n is 1-3 and R is hydrogen (for instance,allyl-benzocyclobutene) are not preferred, as these type of monomers arenot cationically polymerizable.

Any glass-forming monomer known to those of skill in the art can be usedin the polymer. Examples of suitable glass-forming monomers includestyrenic monomers such as styrene, alpha-alkyl styrene (e.g.,alpha-methyl styrene), 4-alkylstyrene, 4-alkoxystyrene, and variousbenzene-ring substituted styrenes. Suitable glass-forming monomers alsoinclude non-reactive glassy compounds such as norbornadiene ornorbornene. The non-reactive glassy compounds are preferably bicyclicbridged systems that obey Bredt's rule, which states that thebridgeheads cannot be involved in a double bond. Compounds falling underthis rule are typically inert. Preferably, the glass-forming monomer isstyrene.

Additional olefins that are cationically polymerizable may also added tothe polymer. For instance, the polymer may contain a plurality ofconstitutional units that include 1,3-dienes, vinyl ethers, N-vinylethers, N-vinyl carbazoles, N-vinyl pyrrolidone, aldehydes, ketones, orcombinations thereof. An embodiment of this invention is directedtowards a polymer in which the alkene component is copolymerized withone or more 1,3-dienes. Preferred 1,3-dienes include isoprene and1,3-butadiene. Because the 1,3-dienes cannot be homopolymerized bycationic polymerization, it is preferable that they are copolymerizedwith isobutylene or another suitable branched alkene.

An embodiment of this invention also relates to a method of preparing apolymer, comprising the step of cationically polymerizing (a) at leastone branched alkene monomer; (b) at least one olefin monomer having apendant benzocyclobutene group; and optionally (c) at least oneglass-forming monomer. In a preferred embodiment, the styrene ispresent.

The cationically polymerizable branched alkene monomer preferablycontains a tertiary carbon on the vinyl group in the alkene. As known bythose of skill in the art, cations are stable on the tertiary carbon dueto the electron-donicity of the surrounding carbons that stabilize thepositive charge of the cation. Polyisobutylene, a preferred branchedalkene monomer, as discussed above, is an example of an alkene monomerpolymerizable by cationic chemical means that contains a tertiarycarbon. Molecules such as propene contain secondary carbons at the vinylgroup and, as known by those of skill in the art, are not cationicallypolymerized.

Secondary carbons on the vinyl group after polymerization undesirablyleave tertiary hydrogens that are easily extracted by simple oxidationmeans or even acid means to form double bonds. Therefore polymers ofalkenes or olefins containing tertiary hydrogens, such as polypropyleneand poly(l-hexene), tend to oxidize over time and become brittle.Consequently, alkenes having secondary carbons are not desirable forcationic polymerization reactions. On the other hand, alkenes containingtertiary carbons will form alternating quaternary carbons uponpolymerizations. Polymers based upon these alternating quaternarycarbons cannot support a double bond on its backbone; therefore, thesepolymers are much more stable over time and are better suited for usessuch as implants, where the polymer should ideally be able to stay inthe host for an extended period of time.

Like the branched alkene, the olefin monomer having a pendantbenzocyclobutene (BCB) group should also be cationically polymerizable.A similar mechanism in the olefin monomer enables this. Olefins having asecondary carbon on the vinyl group are cationically polymerizable ininstances when the electronegativity of the aromatic ring adjacent tothe vinyl group can stabilize the cation. Thus olefins such as4-vinylbenzocyclobutene, discussed above a preferred olefin, can becationically polymerized. These type of olefins can be easilyincorporated into the polymer simply by titrating it into the reactionduring its polymerization. This is different than, for example, theallyl-BCB, which cannot be added to a cationic polymerization, in partbecause the aromatic ring in the BCB is not adjacent to the vinyl group.

Olefins having a pendant BCB and a tertiary carbon on the vinyl groupare also suitable for cationic polymerization even if the vinyl group isnot adjacent to the aromatic ring of the BCB. Tertiary carbons, whichbecome quaternary carbons during polymerization, are stabilized by theelectronegativity of the surrounding carbons. Therefore, olefins havingtertiary carbons on the vinyl carbons can be incorporated into acationic polymerized reaction much in the same manner as the alkenehaving a tertiary carbon is incorporated.2-Methyl-3-(4-benzocyclobutenyl)-propene is an example of this type ofcompound. Also preferred are olefins that draw on the electronegativityof both the surrounding carbons and the aromatic ring, for example2-(4-benzocyclobutenyl)-propene. These type of olefins will cationicallypolymerize as they are stabilized both by the methyl group (as in thiscase of 2-(4-benzocyclobutenyl)-propene) and the aromatic ring.

Method of preparing polymers via cationic polymerization are well knownin the art. During the carbocationic polymerization process, the olefinhaving a pendent BCB group can be added at any time, that is, during thealkene addition, after the alkene polymerization is completed (with orwithout the glass-forming monomer), or both.

The copolymers of the present invention embrace a variety ofconfigurations, for example, cyclic, linear and branched configurations.Branched configurations include star-shaped configurations (e.g.,configurations in which three or more chains emanate from a singleregion), comb configurations (e.g., graft copolymers having a main chainand a plurality of side chains), and dendritic configurations (includingarborescent or hyperbranched copolymers). The copolymers of the presentinvention embrace (a) copolymers comprising one or more chainscontaining repeating constitutional units of a single type (e.g., blockcopolymers), (b) copolymers comprising one or more chains containingrandomly distributed constitutional units of two or more types (e.g.,random copolymers), (c) copolymers comprising one or more chainscontaining two or more types of constitutional units that repeat withinan ongoing series (e.g., alternating copolymers), such as triblocks,quadblocks, and so forth.

For example, in certain beneficial embodiments, the copolymers of thepresent invention are random copolymers containing (a) one or morealkene monomer units, which contain a plurality of units correspondingto one or more branched alkene monomer species and (b) one or moreBCB-olefin monomer units, which contain a plurality of unitscorresponding to one or more BCB-olefin monomer species. Examples ofbranched alkene monomer species and BCB-olefin monomer species arediscussed above.

For another example, in certain beneficial embodiments, the copolymersof the present invention are block copolymers containing (a) one or moreolefin monomer blocks, which contain a plurality of units correspondingto one or more branched alkene monomer species and (b) one or moreBCB-olefin monomer blocks, which contain a plurality of unitscorresponding to one or more BCB-olefin monomer species. Examples ofbranched alkene monomer species and BCB-olefin monomer species arediscussed above. As above, in some embodiments, the BCB-olefin blockscan further contain a plurality of units that correspond toglass-forming monomer species.

The number average molecular weight (Mn) of the block copolymers of thepresent invention typically range, for example, from about 1000 to about2,000,000, more typically from about 10,000 to about 300,000, even moretypically 50,000 to 150,000, with the BCB-olefin units typicallycomprising 0.01-60 mol %, more typically 0.5-40 mol %, even moretypically 0.5-5 mol % of the polymer. In some embodiments, polymers havea narrow molecular weight distribution such that the ratio of weightaverage molecular weight to number average molecular weight (Mw/Mn)(i.e., the polydispersity index) of the polymers ranges from about 1.0to about 2.5, or even from about 1.0 to about 1.2.

Living polymerization, i.e., a polymerization that proceeds in thepractical absence of chain transfer and termination, is a desirableobjective in polymer synthesis. Living cationic polymerization impliesthat a polymer can be grown from one or from a plurality of active sitesin a controlled manner (controlled molecular weight, molecular weightdistribution, end functionalities, etc.). During this growth process,different molecules can be incorporated into the backbone of thepolymer, yielding polymers with well-defined structures. For example,poly(styrene-block-isobutylene-block-styrene) (“SIBS”) is a polymerwhere isobutylene is grown to a certain block size from two ends of adifunctional seed molecule and then styrene is infused into the reactionto cap the growing chain with glass-forming monomer segments. The resultis a thermoplastic triblock polymer ofpolystyrene-polyisobutylene-polystyrene. One of the advantages of thistype of polymer system is that depending upon the molar ratio of styreneto isobutylene, polymers can be made with durometers from Shore 20A toShore 90D with a wide range of elongations. Another advantage of thistriblock over a simple random polymerization of isobutylene and styreneis that the polymer blocks thus formed can segment into differentdomains which dramatically improve physical properties such as tensilestrength, tear strength and compression set.

For certain other embodiments of the invention, when the copolymers ofthe present invention are random copolymer, conventional polymerizationis employed in polymer synthesis. Random copolymers are formed bypolymerizing monomer mixtures of (a) branched alkene monomer species(e.g., isobutylene) and (b) BCB-olefin monomer species (e.g.,4-vinylbenzocyclobutene or 2-(4-benzocyclobutenyl)-propene).

In some embodiments of the present invention, block copolymers areformed by the sequential monomer addition technique using (a) branchedalkene monomer species (e.g., isobutylene) and (b) BCB-olefin monomerspecies (e.g., 4-vinylbenzocyclobutene or2-(4-benzocyclobutenyl)-propene). As above, in some embodiments, amixture of BCB-olefin and glass-forming monomer species may be usedinstead of BCB-olefin monomer species alone.

In one embodiment, the copolymers of the present invention are blockcopolymers containing (a) one or more olefin monomer blocks, whichcontain a plurality of units corresponding to one or more branchedalkene monomer species, such as isobutylene, copolymerized with (b) oneor more BCB-olefin monomer species, to produce a polymer comprised ofpolyisobutylene (or other polyalkene) dispersed with BCB crosslinkableunits. In the presence of heat, for instance temperatures above 180° C.,these polyisobutylene polymers containing BCB crosslinking unitscrosslink into 3-dimensional thermoset materials.

In another embodiment, the copolymers described above containingpolyisobutylene co-polymerized with BCB can be mixed in the melt (below180° C.) with other copolymers. The other copolymer may be, forinstance, block copolymers containing (a) one or more glass-formingmonomer blocks, which contain a plurality of units corresponding to oneor more glass-forming monomer species, such as alpha-methyl styrene,copolymerized with (b) one or more BCB-olefin monomer species to producea copolymer comprised of poly(alpha-methyl styrene) (or otherglass-forming monomer) dispersed with BCB crosslinkable units. In thepresence of heat, for instance temperatures above 180° C., thesepolyisobutylene polymers containing BCB crosslinkable units cancrosslink to the poly(alpha-methyl styrene) polymers containing BCBcrosslinkable units to form 3-dimensional thermoset materials that,depending upon the ratios of the above copolymers, can provide rubberyto stiff materials with exceptional physical and chemical properties.

In many embodiments, the polymer is formed at low temperature from areaction mixture that comprises: (a) a solvent system appropriate forcationic polymerization, (b) one or more branched alkene monomerspecies, (c) an initiator, and (d) a Lewis acid coinitiator. Inaddition, a proton-scavenger is also typically provided to ensure thepractical absence of protic impurities, such as water, which can lead topolymeric contaminants in the final product. An inert nitrogen or argonatmosphere is generally required for the polymerization.

Polymerization can be conducted, for example, within a temperature rangeof from about 0° C. to about −100° C., more typically from about −50° C.to −90° C. Polymerization times are typically those times that aresufficient to reach the desired conversion.

Among the solvent systems appropriate for cationic polymerization, manyof which are well known in the art, are included: (a) C₁-C₄ halogenatedhydrocarbons, such as methyl chloride and methylene dichloride, (b)C₅-C₈ aliphatic hydrocarbons, such as pentane, hexane, and heptane, (c)C₅-C₁₀ cyclic hydrocarbons, such as cyclohexane and methyl cyclohexane,and (d) mixtures thereof. For example, in some beneficial embodiments,the solvent system contains a mixture of a polar solvent, such as methylchloride, methylene chloride and the like, and a nonpolar solvent, suchas hexane, cyclohexane or methylcyclohexane and the like.

Initiators for living carbocationic polymerization are commonly organicethers, organic esters, organic alcohols, or organic halides, includingtert-ester, tert-ether, tert-hydroxyl and tert-halogen containingcompounds. Specific examples include alkyl cumyl ethers, cumyl halides,alkyl cumyl esters, cumyl hydroxyl compounds and hindered versions ofthe same, for instance, dicumyl chloride, 5-tert-butyl,1,3-dicumylchloride, and 5-tert-butyl-1,3-bis(1-methoxy-1-methylethyl)benzene.5-tert-butyl-1,3-bis(1-methoxy-1-methylethyl)benzene is the preferredinitiator for cationic polymerization and may be prepared through themethods disclosed in Wang B. et al., “Living carbocationicpolymerization XII. Telechelic polyisobutylenes by a sterically hinderedbifunctional initiator” Polym. Bull. (1987)17:205-11; or Mishra M. K.,et al., “Living carbocationic polymerization VIII. Telechelicpolyisobutylenes by the MeO(CH₂)₂C-p-C₅H₄—C(CH₃)₂OMe/BCl₃ initiatingsystem” Polym. Bull. (1987) 17:7-13, both of which are hereinincorporated by reference in their entirety. The initiators used forcrosslinkable polyolefins described in this invention include mono ormultifunctional initiators.

Carbocationically terminated star polymers can be formed by selectinginitiators having three or more initiation sites, for example, tricumylchloride (i.e., 1,3,5-tris(1-chloroy-1-methylethyl)benzene), whichcontains three initiation sites.

Examples of Lewis acid coinitiators include metal halides such as borontrichloride, titanium tetrachloride and alkyl aluminum halides. TheLewis acid coinitiator is typically used in concentrations equal to orgreater, e.g., 2 to 50 times greater, than the concentration of theinitiator.

Examples of proton-scavengers (also referred to as proton traps) includesubstituted or unsubstituted 2,6-di-tert-butylpyridines, such as2,6-di-tert-butylpyridine and 4-methyl-2,6-di-tert-butylpyridine, aswell as 1,8-bis(dimethylamino)-naphthalene and diisopropylethyl amine.The concentration of the proton trap is preferably only slightly higherthan the concentration of protic impurities such as water in thepolymerization system.

Further information regarding the preparation of block copolymers frommonomer species that have significantly different reactivities can befound, for example, in United States Patent Application No. 20050187414,herein incorporated by reference in its entirety.

A beneficial aspect of this invention is that the polymers makeexcellent thermoplastics. The resultant thermoplastic polymer can becleaned by multiple dissolution and precipitation procedures, which canbe especially useful in medical applications, as it is still soluble insolvents. In addition, the polymer can then be molded or extruded orcast into its desired shape and then heat cured to react the olefinhaving the pendant BCB group with itself to crosslink the polymer into athermoset shape. The resultant product provides better heat stability,better creep resistance, less water uptake, and less swelling orsolubility in organic solvents. Another advantage of a thermoset polymeris that the polymer can be heat or solvent compounded with plasticizersincluding polyisobutylene, mineral oil, paraffin oil and the like tosoften the polymer.

Once crosslinked, the polymer can be used for heart valves, vertebraldisks, dynamic stabilizers, sealable vascular grafts, stent grafts,intraocular lens (e.g., accommodating intraocular lenses), glaucomadrainage implants, pacemaker headers, pacemaker lead insulators andother implantable medical devices as well as other medical devices whereexceptional compression set or creep resistance are important.Additionally, the polymers have use for various uses outside thebiomedical field, such use as O-rings or as components of windshieldwipers.

The invention is further described with reference to the followingnon-limiting examples.

EXAMPLE 1 Synthesis of poly(st-co-4VBCB)-polyIB-poly(st-co-4VBCB)triblock copolymer

337 mL of methylcyclohexane (MeCHx) were added to a glass reactionvessel equipped with mechanical stirrer, stainless steel serpentinetubing for liquid nitrogen cooling, stainless steel tubing for feedingmethyl chloride (MeCl) and isobutylene (IB) into the vessel, athermocouple with temperature controller, a nitrogen bubbler and anaddition dropping funnel. The liquid was cooled down to −80° C. byliquid nitrogen cooling. Sequentially MeCl (189 g) and IB (20 g) wereadded through the feeding line immersed in the liquid, so that the gasesare condensed into the liquid. While gases were being condensed, aninitiator solution (HDCE/DTBP/MeCHx 0.28 g/0.45 mL/15 mL) was addedthrough a port on the reactor lid. TiCl₄ (3.5 mL, use a 10 cc glasssyringe) was then added through an opening in the reactor lid, whichstarted the IB polymerization (the timer is started). Forty minuteslater, ˜4 mL of reaction mixture was withdrawn from the reactor andquenched in excess methanol. A mixture of styrene/4VBCB/MeCHx (7 mL/2mL/20 mL) was added slowly into the reactor through a syringe in 2minutes. After 6 minutes, the reaction was quenched with excessmethanol. As is well known in the art, the term “HDCE” refers to5-Tert-butyl-1,3-bis(1-methoxy-1-methylethyl)-benzene, also called5-tert-butyl-1,3-dicumyl ether, aka hindered dicumyl ether (HDCE), andthe term “DTBP” refers to 2,6-di-tert-butyl-pyridine.

The reaction mixture was stored under the fume hood overnight. The toplayer was separated and washed repeatedly with distilled water untilneutral. The solution was precipitated into isopropyl alcohol, followedby dissolution in toluene and precipitation in isopropyl alcohol again.The precipitate was dried in a vacuum oven at ˜60° C. until constantweight (yield: 22 g).

The polymer was characterized by GPC and NMR. As shown in FIG. 1, boththe starting PIB (low elution volume) and the triblock copolymer (highelution volume) show a narrow monodispersed peak in GPC RI traces, andthe traces shift smoothly as molecular weight increases. As shown inFIG. 2, there is a singlet at ˜3.1 ppm in proton NMR spectrum, which isattributed to the strained ring of BCB. The broad peaks at ˜6.4-7.3 ppmare attributed to aromatic protons on styrene and 4-VBCB monomer units.From the relative integration intensities, the copolymer was determinedto have ˜3 mol % 4-VBCB and ˜7 mol % styrene.

EXAMPLE 2 Synthesis of poly(IB-co-4VBCB) random copolymer

337 mL of methylcyclohexane (MeCHx) were added to a glass reactionvessel equipped with mechanical stirrer, stainless steel tubing forliquid nitrogen cooling, stainless steel tubing for feeding methylchloride (MeCl) and isobutylene (IB) into the vessel, a thermocouplewith temperature controller, a nitrogen bubbler and an addition droppingfunnel. The liquid was cooled down to −80° C. by liquid nitrogencooling. Sequentially MeCl (189 g) and IB (5 g) were added through thefeeding line immersed in the liquid, so that the gases are condensedinto the liquid. While gases are being condensed, an initiator solution(HDCE/DTBP/MeCHx 0.28 g/0.45 mL/15 mL) was added through a port on thereactor lid. TiCl₄ (3.5 mL, using a 10 cc glass syringe) was then addedthrough an opening in the reactor lid, which starts the IBpolymerization (the timer was started). Five minutes later, 36 g of IBand 1.5 g 4VBCB (dissolved in 10 mL of MeCHx) were added slowly, taking7 min and 9.5 min, respectively. After all 4-VBCB was added, thereaction is kept going for 60 min. Samples were taken at 5, 30 and 60min. The reaction was quenched with excess methanol in the end.

The reaction mixture was stored under the fume hood overnight. The toplayer was separated and washed repeatedly with distilled water untilneutral. The solution was precipitated into isopropyl alcohol, followedby dissolution in hexane and precipitation in isopropyl alcohol again.The precipitate was dried in a vacuum oven at ˜60° C. until constantweight (yield: 35 g).

The polymer was characterized by GPC and proton NMR. GPC RI traces ofthe samples show (see FIG. 3) that the molecular weight increases withreaction time. Little change was observed in molecular weight (˜10%)from 30 min to 60 min, as the polymerization approached completion. Eachsample had a UV signal with similar elution volume as its RI signal(FIG. 3, 4). The sample taken at 5 min exhibited a much stronger UVsignal than the other two, indicating that it has a higher 4-VBCBcontent at lower conversion. The incorporation of 4-VBCB into thecopolymer was further confirmed by proton NMR spectroscopy. A singlet at˜3.1 ppm was seen in proton NMR spectrum (FIG. 5), which is attributedto the strained ring of BCB.

When heated up to 240° C. for 10 min, the copolymer became insoluble inTHF and thus thermally crosslinked.

EXAMPLE 3 Thermal crosslinking ofpoly(st-co-4VBCB)-polyIB-poly(st-co-4VBCB) triblock copolymer

A sample (0.2 g) of the poly(st-co-4VBCB)-polyIB-poly(st-co-4VBCB)triblock copolymer as formed above was placed between two Teflon films,and the films placed between two flat metal plates. The resultingstructure was placed in a hot press (250° C.) for 10 minutes withvirtually no pressure applied. The Teflon films were removed from theplates and cooled to room temperature. A small piece of the heat treatedpolymer was placed in a vial containing THF. The film remained insolubleovernight and longer, indicating that it crosslinked.

Polymer samples were thermally treated at different temperatures for 10minutes. At temperatures above 220° C., the resultant polymer isinsoluble in THF. At a temperature of 200° C., the resultant polymer issoluble in THF. For thermal crosslinking below 220° C., extended timeperiod (>10 min) may be necessary.

EXAMPLE 4 Preparation of a SIBS Triblock Polymer

SIBS was prepared in two steps in one pot. In the first step,isobutylene was polymerized by a 5-tert-butyl,1,3-dicumyl chloride/TiCl₄initiating system in a methyl chloride/hexanes solvent system in thepresence of a proton trap under a blanket of dry nitrogen at −80° C.When the central PIB block reached the desired molecular weight, in thiscase 50 KDaltons, a sample was removed from the reactor and styrene wasadded to the reactor and the polymerization continued until the outerpolystyrene blocks also reach a predetermined length, in this case 75KDaltons. The process was terminated by the addition of methanol. Thesample that was taken was dried in an oven. After drying in the oven,the sample was observed to have a consistency similar to that of arubber band.

EXAMPLE 5 Comparative Example using 1-Hexene

This experiment was run to compare the effect of polyisobutylene, asdescribed in Example 4, with 1-hexene. 1-hexene was dissolved in amethyl chloride/hexanes solvent system and the mixture was added to thereaction pot in the presence of a 5-tert-butyl,1,3-dicumylchloride/TiCl₄ initiating system, also in a methyl chloride/hexanessolvent system, in the presence of a proton trap under a blanket of drynitrogen at −80° C. However, in this case, at the end of the addition, asample was taken which when dry, resembled a lumpy oil. The reactionnever went to completion because to chain termination effects. Thestyrene was never added to the reactor as the experiment was aborted.

Based on these results, it was concluded that 1-hexene could not achievean elastomer by cationic polymerization. Instead, the reaction producedlow molecular weight oils.

In accordance with another aspect of the invention, the polymericmaterial as described herein realizes an intraocular lens (IOL) for thereplacement of the natural crystalline lens of the eye. The naturalcrystalline lens is a gel-like material that sits within the lenscapsule of the eye and when the lens capsule is stretched by thezonules, the gel changes its thickness and therefore its focal pointthereby allowing focusing at different distances. When the natural lensis removed from the lens capsule, lens epithelial cells (LECs) begin tomultiply and spread on the posterior wall of the lens capsule andeffectively render the posterior wall opaque (referred to as “posteriorcapsule opacification” or PCO), which results in impaired vision. TheLEC's also spread on the anterior wall. However, due to the opening inthe anterior wall of the lens capsule (the capsulorrhexus) employed intraditional IOL implantations, there is no wall for them to spread onto.The occurrence of PCO is relatively high in traditional IOLimplantations where the LECs spread between the IOL and the lenscapsule.

In the preferred embodiment, the polymeric material as described hereinis used to form a one-piece IOL that includes an optic portion with anouter peripheral edge as well as one or more haptic elements (orhaptics) that project radially outward from the peripheral edge of opticportion as shown in FIGS. 6-8C.

In the embodiment of FIG. 6, the IOL 100 includes an optic portion 102with an outer peripheral edge 103. Three haptic elements 104A, 104B,104C (collectively, 104) project radially outward from the peripheraledge 103 of optic portion 102. The haptic elements 104 are preferablyintegrally formed with and permanently connected to the outer peripheraledge 103 of optic portion 102. Different haptic designs, such as thosethat utilize two haptics or four haptics can also be used.

In the embodiment of FIGS. 7-8A, the IOL 100′ employs a ring haptic 104′as is well known in the art. FIG. 7 illustrates a top view of the IOL100′ with an optic portion 102″ and a ring haptic 104′. Cross-sectionsfor different embodiments are shown in FIGS. 8A-8C. The front and backsurfaces of optic portion 102′ can be of any diopter (curvature)necessary to provide the desired correction for the patient. Forexample, the front surface of the optic portion 104′ may be convex asshown in FIGS. 8A-8C or possibly concave (not shown). The back surfaceof the optic portion 104′ is preferably flat as shown in FIGS. 8A-8C,but it may be concave or convex to add or subtract magnification. Asshown in FIGS. 8A-C, the angle θ of the annulus of the ring haptic 104′relative to the plane of the optic portion 104′ (which is disposedsubstantially perpendicular to the optical axis of the eye) is between 0and 45 degrees, and more preferably between 10 and 20 degrees, and mostpreferably 15 degrees.

The terminal end(s) of the haptic(s) of the IOL as described herein areadapted to rest in and engage the lens capsule where such terminalend(s) is(are) held in place through compressive forces exerted by theinner surfaces of the lens capsule. The haptic(s) preferably do not liein the plane of the optic portion but are angled relative to the opticportion (for example, at 15 degrees) such that posterior side of theoptics portion presses against and contacts the posterior wall of thelens capsule. This configuration (which is typically referred to as a“vaulted configuration” or “vaulted haptics”) is important because thepressure of the optics portion against the posterior wall of the lenscapsule prevents epithelial cells from migrating between the opticsportion and the posterior wall and thereby mitigates the occurrence ofPCO. Moreover, due to the crosslinked nature of the polymeric materialas described herein, the vaulted haptics realized from such polymericmaterial maintain pressure of the optics portion against the posteriorwall of the lens capsule over time and thus mitigates the occurrence ofPCO over time.

In addition, when accommodation is desired, the haptics of the IOL actas a hinge which allows the optics portion to move forward or backwardsalong the optical axis of the eye. The crosslinked nature of thepolymeric material as described herein allows for such hinged movementwhile providing memory that returns the haptics to their original shapeduring such accommodation. Moreover, the polymeric material as describedherein better resists fatigue under the flex stresses imposed duringaccommodation as compared to the acrylic lenses currently on the market.More specifically, acrylic lenses are not used for accommodating IOLsfor this reason. Typically, silicone is used for accommodating IOLs, butsilicone IOLs are thick In addition, silicone swells when silicone oilis used following victrectomy; that is when the vitreous humor isremoved and replaced with silicone oil, the silicone IOL will swell.Silicone oil has no effect on an IOL realized from the polymericmaterial as described herein.

The polymeric material as described herein provides an index ofrefraction in the range between 1.525 and 1.535 as compared to an indexof refraction between 1.25 and 1.42 for silicone rubber. This higherindex of refraction provides greater magnification as compared tosilicone rubber, which enables the IOL realized from the polymericmaterial described herein to be thinner than silicone rubber IOLs. Athin IOL is advantageous as it can be introduced into lens capsulethrough a smaller size cannula and thus reduces the size of the surgicalincision into the lens capsule. The reduced size incision lessens thechance of an astigmatism that can possibly result therefrom when theincision is sutured closed. Moreover, it is contemplated that the thinIOL can be deployed into the lens capsule through an incision less than2.5 mm. In this case, a suture is not necessary to close the incisionand astigmatisms are not a concern.

In the preferred embodiment, the polymeric material of the IOL includesPIB crosslinked by at least one BCB-olefin monomer as described hereindue to the homogeneity of such material. It is also contemplated thatthe polymeric material of the IOL can be made gel like to form aphako-ersatz lens. In this embodiment, the polymeric material asdescribed herein can be made into a gel for realizing the IOL byblending in, either with heat or in solvent, plasticizers such as lowmolecular weight PIB, mineral oil, paraffin oil, organic solvents(toluene, hexane, heptane, octane, nonane, decane, dodecane, etc.) orany other aliphatic plasticizer. For example, at 90% plasticizer, thepolymeric material as described herein becomes jell-o-like.

When PIB is used as part of the polymeric material of the IOL, the PIBis typically synthesized in organic solvent using a Lewis acid as aninitiator. One such Lewis acid that is preferred for this application istitanium tetrachloride. In order to quench the reaction, chemicals suchas alcohols (methanol, for example) are added in excess to the reactionstoicheometry which immediately quenches the reaction by neutralizingtitanium tetrachloride. At completion of the reaction, titaniumtetrachloride is converted into various salts of titanium, includingtitanium dioxide, titanium methoxide, and the like. In addition,depending upon the reaction vessel used, various salts of titanium canform with materials inherent to the reaction vessel, especially if thevessel is comprised of stainless steel—these salts render the materialblack with time. Nevertheless, a consequence of adding these reactantmaterials is that in order to render the material clean and highlytransparent, these excess materials and their byproducts must be removedfrom the polymer upon completion of the reaction. These remnant saltsand other unwanted chemicals are preferably washed from the PIB materialby washing the polymer in a separatory funnel with salt water, with purewater and with repeated precipitations in excess polar solvent (such asisopopanol, acetone, methanol, ethanol and the like). Other well-knownwashing procedures can also be used. Note that if the material is notwashed of salts, these hygroscopic salts begin to draw in water when thematerial is equilibrated in water. Voids where the salts have beentrapped are readily viewed under scanning electron microscopy and thesevoids become filled with water as the salt is dissolved out. As waterhas a refractive index of approximately 1.33 and material has arefractive index of 1.53, the difference in refractive index issufficient to render the polymer cloudy and at times totally opaque. Ifthe material is washed appropriately, these salts are removed and voidsno longer exist.

When used as an IOL, the polymer can be compounded with radiopaquefillers and the like to enable visualization under X-ray or angiography.Other fillers and additives known in the art of preparing an IOL canalso be added using known techniques and procedures.

There have been described and illustrated herein several embodiments ofpolymers and crosslinked polyolefins for biomedical applications as wellas methods of making same. While particular embodiments of the inventionhave been described, it is not intended that the invention be limitedthereto, as it is intended that the invention be as broad in scope asthe art will allow and that the specification be read likewise. It willtherefore be appreciated by those skilled in the art that yet othermodifications could be made to the provided invention without deviatingfrom its spirit and scope as claimed.

What is claimed is:
 1. A method of preparing a thermoplastic copolymercomprising: cationic polymerizing a mixture including i) at least onebranched alkene monomer, ii) at least one olefin monomer having apendant benzocyclobutene (BCB) group, and iii) at least one initiatorsuitable for cationic polymerization of the mixture to form thethermoplastic copolymer; wherein the thermoplastic copolymer formed bycationic polymerization of the mixture comprises a random distributionof a plurality of constitutional units that include constitutional unitscorresponding to the at least one branched alkene monomer of i) andconstitutional units corresponding to the at least one olefin monomerhaving a pendant benzocyclobutene (BCB) group of ii); and wherein thebranched alkene monomer of i) is an isoolefin selected from the groupconsisting of isobutylene, 2-methyl-1-butene, 2-methyl-1-pentene,2-methyl-1-hexene, and combinations thereof.
 2. A method according toclaim 1, wherein: the isoolefin is isobutylene.
 3. A method according toclaim 1, wherein: the at least one olefin monomer having a pendant BCBgroup includes a monomer having the formula

wherein R is hydrogen or an alkyl group and n is
 0. 4. A methodaccording to claim 3, wherein: the at least one olefin monomer having apendant BCB group includes 4-vinylbenzocyclobutene or2-(4-benzocyclobutenyl)-propene.
 5. A method according to claim 1,wherein: the at least one olefin monomer having a pendant BCB groupincludes a monomer having the formula

wherein R is alkyl group and n is an integer ranging from 0-3.
 6. Amethod according to claim 5, wherein: the at least one olefin monomerhaving a pendant BCB group includes2-methyl-3-(4-benzocyclobutenyl)-propene.
 7. A method according to claim1, wherein: the thermoplastic copolymer further includes a glass-formingmonomer selected from the group consisting of styrene, indene,α-methylstyrene, p-tert-butylstyrene, p-chlorostyrene, norbornene, andcombinations thereof.
 8. A method according to claim 7, wherein: theglass-forming monomer is styrene.
 9. A method according to claim 1,wherein: the at least one olefin monomer having a pendant BCB group ispresent in amount ranging from 0.01 to 60 mol % of the monomeric unitsof the thermoplastic polymer.
 10. A method according to claim 1,wherein: the cationic polymerizing involves living cationicpolymerization.
 11. A method according to claim 1, wherein: thethermoplastic copolymer undergoes crosslinking when exposed totemperatures of at least 180° C.
 12. A method according to claim 1,wherein: the at least one initiator comprises a Lewis acid initiator.13. A method according to claim 1, wherein: the at least one branchedalkene monomer of i) and the at least one olefin monomer having apendant benzocyclobutene (BCB) group of ii) are added contemporaneouslyto the mixture during the cationic polymerizing of the mixture.
 14. Amethod of preparing a thermoset polymer comprising: processing athermoplastic copolymer prepared according to claim 1 to form aresultant thermoset polymer, wherein the processing includes heating thethermoplastic copolymer such that thermoplastic copolymer undergoescrosslinking to form the resultant thermoset polymer.
 15. A method ofpreparing an implantable medical device comprising: processing athermoplastic copolymer prepared according to claim 1 to form at leastpart of the implantable medical device, wherein the processing includesheating the thermoplastic copolymer such that the thermoplasticcopolymer undergoes crosslinking to form a resultant thermoset polymerthat is part of the implantable medical device.
 16. A method accordingto claim 15, wherein: the implantable medical device comprises anintraocular lens.